ABSTRACT Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in people greater than 60 years of age in industrialized countries. Worldwide, it is estimated that nearly 300 million people will have some form of AMD by 2040. Thus far, no effective treatment exists for halting dry AMD progression, the form which affects 90% of all AMD patients. The only suggestion for slowing this form of AMD is to take high-dose vitamin and mineral supplements daily. Emerging evidence suggests that mutations or alterations in fibulin-3 (F3), a secreted protein of unknown function, plays a prominent role in influencing the pathogenesis of macular degenerative diseases. One specific example is how an R345W mutation in F3 causes an early onset macular dystrophy called Malattia Leventinese (ML), which is characterized by complement activation, production of inflammatory cytokines, as well as sub-retinal pigment epithelium (RPE) deposits. However, in general, there is a lack of knowledge regarding how these macular degenerations develop. Furthermore, there are no effective treatments for either ML or the more prevalent disease, dry AMD. Therefore, there is an urgent need to develop a mechanistic understanding of the underlying causes of AMD-like diseases, such as ML, and to identify new therapies for them. In this proposal we plan to i) test genetic strategies directed at preventing the secretion of misfolded R345W F3 from RPE cells, ii) employ a novel, conditional approach to regulate inflammatory signaling downstream of R345W F3 misfolding, and iii) test whether WT F3 is also necessary for sub-RPE deposit formation. At the end of the study, we hope to have a better understanding of the molecular basis by which misfolded F3-facilitates inflammation and sub-RPE protein deposition, and to identify a number of therapeutically- tractable approaches for treating ML. The insight that we gain regarding how misfolded F3 is involved in triggering inflammation and sub-RPE deposits can likely be applied more broadly to prevalent retinal diseases such as dry AMD.